Ischemic heart disease remains the most common cause ofdeath in the United States. For many years, metabolic protection of the ischemic heart has been an important but elusive goal in the treatment of myocardial ischemia. Acute myocardial ischemia adversely alters both myocardial energy substrate metabolism and contractile function; in fact, these abnormalities are related, suggesting the potential importance of metabolic intervention in ischemic heart disease.
The abnormalities of myocardial substrate metabolism observed during ischemia and during reperfusion are different. During ischemia, myocardial oxygen supply is limited and anaerobic (glycolytic) metabolism becomes a relatively more important mechanism of ATP synthesis. The energy sources for anaerobic glycolysis are exogenous glucose and myocardial glycogen. In experimental models of low-flow ischemia, interventions that increase availability and myocardial uptake of exogenous glucose and/or pre-ischemic myocardial glycogen content result in greater postischemic recovery of contractile function (1,2).
During reperfusion, an adequate supply of oxygen is delivered to the myocardium, but glucose oxidation remains depressed (3). The hallmark of this abnormality is that a disproportionate fraction of myocardial glucose uptake continues to undergo anaerobic glycolysis to lactate (4). In the absence of irreversible ischemic injury, oxidation of fatty acids and oxygen consumption by reperfused myocardium usually remains normal, or even increased (5). These findings indicate preserved flux through the TCA cycle and electron transport chain. Therefore, the most likely explanation for the characteristic depression of glucose oxidation in reperfused myocardium is diminished activity of pyruvate dehydrogenase.
Fatty acids contribute to the deleterious effects of ischemia and reperfusion on the myocardium. Uptake of FFA is proportional to circulating FFA concentrations (6), which rise in acute myocardial infarction (7). Myocardial uptake of FFA and accumulation of FFA metabolites during ischemia may exert a direct, deleterious effect on mitochondrial function, ion channels, and the recovery of contractile function after reperfusion (8). Furthermore, there is a reciprocal relation between myocardial oxidation of FFA and carbohydrates: Increased utilization of FFA increases mitochondrial acetyl-CoA and NADH, both of which inhibit pyruvate dehydrogenase (9). Therefore, an intervention that reduces circulating FFA concentrations, myocardial FFA uptake and metabolism will indirectly promote oxidation of glucose. In sum, an ideal metabolic intervention would promote myocardial glucose uptake prior to and during ischemia, promote myocardial glucose oxidation during reperfusion, and reduce circulating FFA concentrations and/or myocardial FFA uptake during ischemia.
Among the pharmacologic interventions that have been employed to improve myocardial metabolism during and following acute ischemia are glucose and insulin, agents that stimulate pyruvate dehydrogenase activity (e.g., pyruvate, dichloroacetate), other agents that enhance glucose oxidation and/or reduce FFA oxidation (e.g., ranolazine, trimetazidine, L-camitine), and inhibitors of FFA oxidation (e.g., oxfenicine, etomoxir). Several of these agents have yielded initial positive results in experimental myocardial ischemia and/or clinical studies in patients with ischemic heart disease; however, their further development and application have been limited by discordant findings in isolated heart versus in vivo models or by difficulties in administering the agent in the clinical setting.
Infusion of glucose and insulin (`GIK` when used with potassium in vivo) is the prototype metabolic intervention in myocardial ischemia. Pre-ischemic treatment with glucose and insulin increases myocardial glycogen stores, treatment during ischemia enhances anaerobic glycolytic energy generation, and treatment during reperfusion may also enhance myocardial glucose metabolism (10). GIK has been shown to limit experimental myocardial infarct size and to improve recovery of contractile function after ischemia in isolated, perfused hearts (11).
Recently, our laboratory demonstrated that GIK significantly improves recovery of both systolic and diastolic function following regional low-flow ischemia in vivo in pigs (12). GIK appeared promising in several early clinical trials (13), but its clinical application has not advanced because it cannot be applied in an anticipatory manner and requires careful monitoring to avoid excessive hyperglycemia or hypoglycemia.
Dichloroacetate and pyruvate stimulate the activity of pyruvate dehydrogenase, increase carbohydrate oxidation, and improve post-ischemic recovery of cardiac function in animal models (14). However, clinical application of these agents has been impeded by short half life and the requirement for millimolar blood concentrations to achieve optimal treatment effect (15).
Ranozaline and trimetazidine both increase myocardial glucose oxidation and reduce FFA oxidation after ischemia in isolated perfused rat hearts, and appear to limit angina and exercise-induced ECG changes in small clinical trials of patients with ischemic heart disease (16-19). These drugs appear to increase glucose oxidation and reduce FFA oxidation, perhaps through an effect on PDH. However, neither of these agents has been effective in reducing post-ischemic myocardial contractile dysfunction or infarct size in large animal in vivo models (20,21).
L-carnitine has been shown to augment myocardial glucose metabolism during and following experimental ischemia, and to attenuate left ventricular dilatation and remodeling after myocardial infarction in patients (22,23). However, this agent also has been disappointingly ineffective in attenuating contractile dysfunction after experimental low-flow ischemia in vivo (24).
Inhibitors of FFA metabolism such as oxfenicine have been shown to attenuate post-ischemic dysfunction in some in vivo studies (25) but not others (26) and have been shown to promote potentially deleterious accumulation of myocardial lipid and to cause chronic mitochondrial dysfunction (27,28).
TABLE 1 ______________________________________ Previously Employed Metabolic Strategies in Myocardial Ischemia Treatment Drawbacks for Clinical Application ______________________________________ GIK IV administration Difficult to use in anticipatory fashion Careful monitoring required Dichloroacetate IV administration Pyruvate Difficult to use in anticipatory fashion Millimolar concentration required Ranolazine no convincing evidence of improved post-ischemic Trimetazidine recovery of LV function in vivo L-carnitine Inhibitors of FFA no consistent evidence of improved post-ischemic metabolism function accumulation of myocardial lipid possible chronic mitochondrial damage ______________________________________
Thus, despite the interest in and potential importance of metabolic intervention in ischemic heart disease, there is currently no clearly effective and readily applicable agent for clinical use in acute myocardial ischemia.
The present invention relates to a new use for a series of known compounds, including thiazolidinedione compounds, oxazolidinedione compounds, isoxazolidinedione compounds and oxadiazolidinedione compounds, in the treatment of myocardial ischemia and reduction or prevention of myocardial ischemia associated dysfunction. We have now surprisingly discovered that the class of compounds now known as "insulin sensitizers", and which includes various thiazolidinedione compounds, oxazolidinedione compounds, isoxazolidinedione compounds and oxadiazolidinedione compounds, has the ability to reduce mechanical (systolic and diastolic) and/or metabolic dysfunction consequent to myocardial ischemia. In addition, we have found these compositions effective for enhancing insulin sensitivity to supranormal levels and reducing hypertension in hypertensive patients determined to be non-diabetic and/or have normal insulin sensitivity.